Percutaneous medical devices such as central venous catheters, peritoneal dialysis catheters, and intraosseointegrated implants are ubiquitous in modern healthcare despite the fact that there is a large risk of infection. The integration of synthetic devices with the human body in order to reduce the infection burden is a long-term goal that will vastly improve the value in employing percutaneous implants. Leveraging tissue regeneration strategies will lead to stable tissue-device interfaces and therefore will function as robust immunoisolation barriers. Biodegradable elastomers will be used as the bulk material in percutaneous implants because of the ability to match the mechanical properties of the polymer with the native skin. One current hypothesis is that cutaneous regeneration can be achieved by modulating macrophage phenotype. The upregulation of restorative macrophage populations may lead to enhanced keratinocyte migration, extracellular matrix deposition, and stable vascularization. Injurious responses such as inflammation and scarring in can be suppressed by reducing the population of inflammatory macrophages. This hypothesis will be tested by completing the specific aims described in this proposal. Briefly, biodegradable elastomers will be synthesized and used as drug-eluting percutaneous implants. A two-phase controlled release system will be designed to deliver small molecule agonists to induce restorative macrophages over a 6-week time period. This system will be validated by differentiating monocytes into restorative macrophages in vitro as assessed by flow cytometry, fluorescence microscopy, and cytokine profiling. The release kinetics, macrophage phenotypes, and gross tissue remodeling will be correlated in vivo. The relative roles of restorative versus inflammatory macrophages in vascular remodeling will be elucidated. The completion of this proposal will be instrumental in validating the general concept of controlling broad scale wound repair and tissue generation using small molecule signaling molecules to control macrophage phenotype. This approach could be applied to a wide range of other tissue models and could potentially be adopted as a novel strategy in tissue engineering and regenerative medicine. Furthermore, the knowledge gained from this proposed research will elucidate the emerging role of monocytes and macrophages in tissue repair and regeneration.